Fatigue of single frog muscle fibers appeared as a decline in tension output during prolonged tetanic stimulation. The concentration of ATP (energy source for contraction) remained normal in fatigued fibers. Furthermore, ATP was not sequestered or unavailable for contraction. Fatigue therefore was due to an inability of the muscle to use energy in the form of ATP. We suggest that H ion as lactic acid, accumulated in these fibers so as to interfere with excitation-contraction coupling. The perineurial sheath which surrounds peripheral nerve axons may regulate nerve function and development. Perineurial permeability was measured for the first time (to 14C-sucrose) and was found to be very low, supporting a regulatory role for the sheath. Permeability was increased by stretch and by soaking in hypertonic solutions. Morphological studies showed that the perineurium can vary in number of cell layers, and that the most internal layers act as a barrier to lanthanum and horseradish peroxidase, due to tight junctions between the cells.